Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity.
Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy.
As announced by the company in a press release earlier this week,
“Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.”
The press release also describes the new compound ZGN-1061 as a,
“…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class. Like other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source. ZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.”
According to the press release,
“The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.”
Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway.
Disclaimer: I have served as a consultant to Zafgen.
That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation.
Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation.
For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum.
During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight.
Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study.
Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability.
Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults.
Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption.
A popular narrative by proponents of low-glycemic index foods is the notion that high-glycemic index foods lead to a surge in plasma glucose, which in turn stimulates a spike in insulin levels, resulting in a rapid drop in blood glucose levels and an increase in appetite (“crash and crave”).
While this narrative is both biologically plausible and has been popularised by countless low-GI diets and products, the actual science of whether this story really holds true is less robust that you may think.
Now, a study by Bernd Schultes and colleagues, published in Appetite, seriously challenges this narrative.
The study was specifically designed to test the hypothesis that inducing glycemic fluctuations by intravenous glucose infusion is associated with concurrent changes in hunger, appetite, and satiety.
Using a single blind, counter-balanced crossover study in 15 healthy young men, participants were either given an i.v. infusion of 500 ml of a solution containing 50 g glucose or 0.9% saline, respectively, over a 1-h period.
On each occasion, the infusions were performed one hour after a light breakfast (284 kcal).
I.v. glucose markedly increased glucose and insulin concentrations (peak glucose level: 9.7 vs. 5.3 mmol/l in the control group); peak insulin level: 370 vs. 109) followed by a sharp decline in glycaemia to a nadir of 3.0 in the glucose study vs. 3.9 mmol/l at the corresponding time in the control condition.
Despite this wide glycemic fluctuation in the glucose infusion condition, the subjective feelings of hunger, appetite satiety, and fullness did not differ from the control condition throughout the experiment.
Clearly, these findings speak against the conventional narrative that fluctuations in glycemia and insulinemia represent major signals in the short-term regulation of hunger and satiety.
Or, as the authors put it,
Our findings might also challenge the popular concept of low glycemic index diets to lose body weight. Advocates of this dietary approach often argue that large glycemic (and concurrent insulinemic) fluctuations induced by the intake of high glycemic index foods can trigger feelings of hunger and, thus, on the long run favor weight gain. Our results argue against this notion since the sharp drop in circulating glucose after the end of the glucose infusion remained without effect on hunger ratings, at least within the time period covered by our experiment.
As they further note, these findings may explain why,
“…several clinical dietary intervention trials have failed to show an advantage of low glycemic index dietary approaches for weight loss in overweight/obese subjects in comparison with other dietary approaches.”
The lesson here, I guess is that, just because there is a seemingly compelling narrative to support an idea, it does not mean that that’s how biology in real life actually works.
Next, in my miniseries on arguments to support calling obesity (defined as excess or abnormal body fat that affects your health), I turn to the impact on health care providers.
Currently, most health care practitioners will happily limit their role in obesity management to warning their patients about the many health consequences of carrying excess weight and advise them to lose weight. They do not, however, see it as their job to actually provide treatment.
This is in stark contrast to diabetes or hypertension, where doctors do see helping patients control their blood glucose or blood pressure levels as an essential part of their job. Here, simply telling patients that they need to lower their blood glucose or blood pressure would not be deemed enough. Helping patients control their blood glucose or blood pressure, happens to be an important part of their job description.
One reason that health care providers have gotten away with simply telling patients to lose weight without actually helping them do so, is precisely because they have never viewed obesity as a disease. Rather, they (as much of the public) have looked at excess weight (and weight loss) as simply a matter of personal “lifestyle” – something that people with obesity should be able to manage on their own.
This, incidentally is one of the main reasons why many doctors are not happy with obesity being called a disease. I have actually heard a colleague ask me, “Why should this be my job? Why can’t they (sic) just eat less and move more – how difficult can that be?”.
That, is exactly the attitude adjustment that calling obesity a chronic disease can change. Perhaps not in the generation of doctors and other health professionals who have grown up thinking of obesity as a “lifestyle choice”. But hopefully, in the next generation of health care providers, for whom treating and helping their patients manage their obesity will be no different from treating and helping patients living with any other chronic disease.
Continuing in my miniseries on why obesity (defined here, as excess or abnormal body fat that affects your health) should be considered a disease, is the simple observation that obesity responds less to lifestyle treatments than most people think.
Yes, the internet abounds with before and after pictures of people who have “conquered” obesity with diet, exercise, or both, but in reality, long-term success in “lifestyle” management of obesity is rare and far between.
Indeed, if the findings from the National Weight Control Registry have taught us anything, it is just how difficult and how much work it takes to lose weight and keep it off.
Even in the context of clinical trials conducted in highly motivated volunteers receiving more support than you would ever be able to reasonably provide in clinical practice, average weight loss at 12 – 24 months is often a modest 3-5%.
Thus, for the vast majority of people living with obesity, “lifestyle” treatment is simply not effective enough – at least not as a sustainable long-term strategy in real life.
While this may seem disappointing to many (especially, to those in the field, who have dedicated their lives to promoting “healthy” lifestyles as the solution to obesity), in reality, this is not very different from the real-life success of “lifestyle” interventions for other “lifestyle” diseases.
Thus, while there is no doubt that diet and exercise are important cornerstones for the management of diabetes or hypertension, most practitioners (and patients) will agree, that very few people with these conditions can be managed by lifestyle interventions alone.
Indeed, I would put to you that without medications, only a tiny proportion of people living with diabetes, hypertension, or dyslipidemia would be able to “control” these conditions simply by changing their lifestyles.
Not because diet and exercise are not effective for these conditions, but because diet and exercise are simply not enough.
The same is true for obesity. It is not that diet and exercise are useless – they absolutely remain a cornerstone of treatment. But, by themselves, they are simply not effective enough to control obesity in the vast majority of people who have it.
This is because, diet and exercise do not alter the biology that drives and sustains obesity. If anything, diet and exercise work against the body’s biology, which is working hard to defend body weight at all costs.
Thus, it is time we accept this reality and recognise that without pharmacological and/or surgical treatments that interfere with this innate biology, we will not be able to control obesity in the majority of patients.
Whether we like it or not, I predict that within a decade, clinical management of obesity will look no different than current management of any other chronic disease. Most patients will require both “lifestyle” and probably a combination of anti-obesity medications to control their obesity.
This does not take away from the importance of diet and exercise – as important as they are, they are simply not enough.
Despite what “lifestyle” enthusiasts will have us believe, diet and exercise are no more important (or effective) for the treatment of obesity, than they are for the treatment of hypertension, diabetes, dyslipidemia, depression, or any other condition that responds to “lifestyle” interventions.
In the end, most patients will require more effective treatments to manage their obesity and all of the comorbidities that come with it. The sooner we develop and make accessible such treatments, the sooner we can really help our patients.